rs763150678

Positions:

• chr21-42383138-G-C
• chr21-42383138-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001256317.3(TMPRSS3):​c.677C>G​(p.Ser226Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S226L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.638

Genes affected

TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity TMPS3_HUMAN there are 56 pathogenic changes around while only 8 benign (88%) in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27379477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.677C>G	p.Ser226Trp	missense_variant	8/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.677C>G	p.Ser226Trp	missense_variant	8/13
TMPRSS3	NM_032405.2	c.677C>G	p.Ser226Trp	missense_variant	8/9
TMPRSS3	NM_032404.3	c.296C>G	p.Ser99Trp	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.677C>G	p.Ser226Trp	missense_variant	8/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.81	T;.;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M;M;M;.;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
Polyphen		0.66	P;P;P;.;P
Vest4		0.32, 0.33, 0.32
MutPred		0.67		Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);
MVP		0.74
MPC		0.15
ClinPred		0.40	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763150678; hg19: chr21-43803247;